Gastric inhibitory peptide (GIP) is a 42-amino acid hormone secreted by the K-cell, a specific intestinal endocrine cell, and was named for its ability to inhibit acid secretion. While several studies have supported the role of GIP as an inhibitor of gastric acid secretion, others have challenged this notion, and currently the precise physiological relationship between GIP and gastric function has not been resolved. In addition to its purported inhibitory effects in the stomach, GIP stimulates insulin release from pancreatic beta-islet cells, and it has been proposed that the peptide plays a physiological role in maintaining glucose homeostasis. Accordingly, the hormone is now often referred to as "glucose-dependent insulinotropic peptide," conserving the original acronym. However, its specific contribution to the maintenance of glucose metabolism and the precise relationship of GIP to glucagonlike peptide-1(7-36) (GLP-1) and other physiological stimulants of pancreatic insulin release is unknown. Much of the uncertainty regarding the exact physiological role of GIP stems from a failure to distinguish physiological from pharmacological effects of the peptide. In addition, significant structural homology among related peptides, such as GIP and GLP-1, often contributes to the ambiguity surrounding the attribution of physiological properties to one or both peptides. Such uncertainty has been a traditional problem when investigating new candidate peptide hormones, and the availability of specific competitive receptor antagonists to several peptides has proven invaluable in facilitating their investigation. This laboratory has recently synthesized and characterized a specific GIP antagonist which will be used in the studies outlined in this proposal to determine the precise physiological role of this important regulatory peptide. Specifically, the aims of this project are: 1) To determine the role of GIP in the physiological regulation of nutrient-stimulated gastric acid secretion; 2) To characterize the relative contribution of GIP release in response to glucose- and lipid-containing meals, in stimulating pancreatic insulin release under physiological and pathological conditions. During the course of these studies, the precise relationship of GIP to GLP-1, another candidate incretin, will be determined; and 3) To determine the mechanisms involved in physiological feedback inhibition of GIP, including the possibility that GIP may autoregulate its own expression, and whether feedback inhibition might also be dependent on circulating glucose or insulin. The proposed studies should provide an important foundation of information to facilitate the determination of the precise role of GIP as a modulator of acid secretion and of glucose metabolism under both physiological and pathological conditions. Moreover, because of the close structural and functional relationship of GIP to other GI peptides, these studies will advance our general understanding of disorders characterized by abnormalities in gastric function and glucose homeostasis.